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Nature. 2014 Sep 25;513(7519):559-63. doi: 10.1038/nature13490. Epub 2014 Jul 13.

Functional polarization of tumour-associated macrophages by tumour-derived lactic acid.

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  • 11] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA [2] Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520-8059, USA [3] Yale-New Haven Transplantation Center, Yale University School of Medicine, New Haven, Connecticut 06519-1369, USA [4] Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8028, USA.
  • 2Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA.
  • 31] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA [2] Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8035, USA.
  • 4Department of Chemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8107, USA.
  • 5Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA.
  • 61] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA [2] Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8028, USA [3] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.

Abstract

Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their 'client cells': namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1α (HIF1α). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.

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PMID:
25043024
[PubMed - indexed for MEDLINE]
PMCID:
PMC4301845
Free PMC Article

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